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Recently, we reported that during the hypertrophic phase (230 days old) of hereditary cardiomyopathy of the hamster (HCMH), short-term treatment (20 days) with 250 mg/kg/day of taurine prevents the development of hypertrophy in males but not in females. However, the mortality rate in non-treated animals was higher in females than in males. To verify whether the sex-dependency effect of taurine is due to the difference in the disease's progression, we treated the 230-day-old animals for a longer time period of 122 days. Our results showed that long-term treatment with low and high concentrations of taurine significantly prevents cardiac hypertrophy and early death in HCMH males (p < 0.0001 and p < 0.05, respectively) and females (p < 0.01 and p < 0.0001, respectively). Our results demonstrate that the reported sex dependency of short-term treatments with taurine is due to a higher degree of heart remodeling in females when compared to males and not to sex dependency. In addition, sex-dependency studies should consider the differences between the male and female progression of the disease. Thus, long-term taurine therapies are recommended to prevent remodeling and early death in hereditary cardiomyopathy. [ABSTRACT FROM AUTHOR]

Endocardial endothelium (EE) is a layer of cells covering the cardiac cavities and modulates cardiomyocyte function. This cell type releases several cardioactive factors, including Angiotensin II (Ang II). This octopeptide is known to induce cardiac hypertrophy. However, whether this circulating factor also induces EE hypertrophy is not known. Taurine is known to prevent cardiac hypertrophy. Whether this endogenous antioxidant prevents the effect of Ang II on human EE (hEE) will be verified. Using quantitative fluorescent probe imaging for calcium and reactive oxygen species (ROS), our results show that Ang II induces (10−7 M, 48 h treatment) an increase in hEE cell (hEEC) volume and its nucleus. Pretreatment with 20 mM of taurine prevents morphological remodeling and increases intracellular calcium and ROS. These results suggest that the reported Ang II induces cardiac hypertrophy is associated with hEEC hypertrophy. This later effect is prevented by taurine by reducing intracellular calcium and ROS overloads. Thus, taurine could be an excellent tool for preventing Ang II-induced remodeling of hEECs. [ABSTRACT FROM AUTHOR]

Our recent work showed that short-term treatment (1–2 days) with high sodium salt had no effect on the morphology of human vascular smooth muscle cells (hVSMCs). However, chronic (long-term treatment, 6–16 days) high sodium salt (CHSS) induced hypertrophy and decreased the relative density of the glycocalyx in hVSMCs. Whether this CHSS effect is reversible at both the morphological and the intracellular calcium and sodium levels is unknown. In the present study, we tested the hypothesis that the effect of CHSS on the morphological and functional levels of hVSMCs is reversible. However, it induced an irreversible increase in the sensitivity of the cells following short-term treatment with high extracellular Na+. We tested the effects of the removal of CHSS treatment on the morphology and intracellular sodium and calcium of hVSMCs. Our results showed that restoring average sodium concentration (145 mM) modeled back the relative density of the glycocalyx, the intracellular resting calcium and sodium levels, and the whole cell and nuclear volumes of hVSMCs. In addition, it induced a permanent remodeling of hVSMCs' response to a short-term increase in the extracellular level of sodium salt by developing spontaneous cytosolic and nuclear calcium waves. Our results showed that CHSS is reversible at both the morphological and basal intracellular ionic levels. However, it maintained a high sensitivity to short-term elevation of extracellular sodium. These results suggest that even if chronic high salt is corrected, it induces a high sodium salt-like sensitive memory. [ABSTRACT FROM AUTHOR]

Calcium is a highly positively charged ionic species. It regulates all cell types' functions and is an important second messenger that controls and triggers several mechanisms, including membrane stabilization, permeability, contraction, secretion, mitosis, intercellular communications, and in the activation of kinases and gene expression. Therefore, controlling calcium transport and its intracellular homeostasis in physiology leads to the healthy functioning of the biological system. However, abnormal extracellular and intracellular calcium homeostasis leads to cardiovascular, skeletal, immune, secretory diseases, and cancer. Therefore, the pharmacological control of calcium influx directly via calcium channels and exchangers and its outflow via calcium pumps and uptake by the ER/SR are crucial in treating calcium transport remodeling in pathology. Here, we mainly focused on selective calcium transporters and blockers in the cardiovascular system. [ABSTRACT FROM AUTHOR]

The vascular endothelium plays a vital role during embryogenesis and aging and is a cell monolayer that lines the blood vessels. The immune system recognizes the endothelium as its own. Therefore, an abnormality of the endothelium exposes the tissues to the immune system and provokes inflammation and vascular diseases such as atherosclerosis. Its secretory role allows it to release vasoconstrictors and vasorelaxants as well as cardio-modulatory factors that maintain the proper functioning of the circulatory system. The sealing of the monolayer provided by adhesion molecules plays an important role in cardiovascular physiology and pathology. [ABSTRACT FROM AUTHOR]

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Premature death due to heart failure is a major health problem. Taurine is a non-essential amino acid that has received much attention. However, although many studies have been carried out on the beneficial effects of taurine in cardiac pathophysiology, no studies have investigated the effect of taurine treatment on the development of hereditary cardiomyopathy (HCM) associated with hypertrophy, heart failure, and early death. This study aims to verify whether short-term treatment (20 days) with taurine in tap water prevents the development of hypertrophy and premature death in hereditary cardiomyopathy of the hamster (HCMH) of the line UM-X7.1 and if its effect is sex-dependent. Our results show that treatment for 20 days with taurine (250 mg/kg/day or 25 mg/animal/day) during the development of the hypertrophic phase (220 days old) significantly decreased (p < 0.01) the heart weight to body weight ratio in male HCMHs without affecting the female. During the 20 days (220–240 days old), there were nearly 40% premature deaths in non-treated males HCMHs and 50% in female HCMHs. Treatment for 20 days wholly and significantly prevented early death in both males and females HCMHs. Our results demonstrate that short-term treatment with taurine prevents the development of cardiac hypertrophy associated with HCM in a sex-dependent manner; however, it prevents early death in a sex-independent fashion. Our results suggest that taurine supplementation could be used to treat HCM. [ABSTRACT FROM AUTHOR]

It is well accepted that hypertension may lead to the development of heart failure (HF). However, little is known about the development of hypotension that may contribute to the onset of hereditary cardiomyopathy (HCM), thus promoting heart failure and early death. The purpose of this study is to verify whether a decrease in blood pressure takes place during different phases of HCM (asymptomatic, necrosis, hypertrophy, and heart failure). Using the well-known animal model, the UM-X7.1 hamster strain of HCM (HCMH), our results showed the absence of a change in mean arterial pressure (MAP) during the asymptomatic phase preceding the development of necrosis in HCMHs when compared to age-matched normal hamster (NH). However, there was a progressive decrease in MAP that reached its lowest level during the heart failure phase. The MAP during the development of the necrosis phase of HCM was accompanied by a significant increase in the level of the sodium–hydrogen exchanger, NHE1. Treatments with the potent NHE1 inhibitor, EMD 87580 (rimeporide), did not affect MAP of NH. However, treatments with EMD 87580 during the three phases of the development of HCM significantly reversed the hypotension associated with HCM. Our results showed that the development of HCM is associated with hypotension. These results suggest that a decrease in blood pressure could be a biomarker signal for HCM leading to HF and early death. Since the blockade of NHE1 significantly but partially prevented the reduction in MAP, this suggests that other mechanisms can contribute to the development of hypotension in HCM. [ABSTRACT FROM AUTHOR]

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Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Endocardial endothelial cells constitute a barrier between the circulating blood and ventricular cardiomyocytes. Although recently our group demonstrated the importance of this type of endothelial cells in excitation-secretion coupling, there is no information on whether this type of cells contributes to cardiac pathologies such as cardiac hypertrophy. Using the well-known model of human hypertrophy and heart failure, the UM-X7.1 hereditary cardiomyopathic hamster, our results showed that during the phase of necrosis and in the absence of cardiac hypertrophy, isolated endocardial endothelial cells underwent a significant increase in cell volume compared to cells isolated from age-matched normal hamsters. This increase of the volume of endocardial endothelial cells persisted during the development of cardiac hypertrophy in the hereditary cardiomyopathic hamster. These results demonstrate for the first time, that endocardial endothelial hypertrophy precedes the development of hypertrophy in hereditary cardiomyopathy and may, via its released factors, contribute to the development of cardiac hypertrophy. These results demonstrate the importance of endocardial endothelial cells in cardiac diseases such as hypertrophy. This type of cells constitutes a new target for understanding hypertrophy and heart failure. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Plasma membrane endothelin type A (ETA) receptors are internalized and recycled to the plasma membrane, whereas endothelin type B (ETB) receptors undergo degradation and subsequent nuclear translocation. Recent studies show that G protein-coupled receptors (GPCRs) and ion transporters are also present and functional at the nuclear membranes of many cell types. Similarly to other GPCRs, ETA and ETB are present at both the plasma and nuclear membranes of several cardiovascular cell types, including human cardiac, vascular smooth muscle, endocardial endothelial, and vascular endothelial cells. The distribution and density of ETARs in the cytosol (including the cell membrane) and the nucleus (including the nuclear membranes) differ between these cell types. However, the localization and density of ET-1 and ETB receptors are similar in these cell types. The extracellular ET-1-induced increase in cytosolic ([Ca]c) and nuclear ([Ca]n) free Ca2+ is associated with an increase of cytosolic and nuclear reactive oxygen species. The extracellular ET-1-induced increase of [Ca]c and [Ca]n as well as intracellular ET-1-induced increase of [Ca]n are cell-type dependent. The type of ET-1 receptor mediating the extracellular ET-1-induced increase of [Ca]c and [Ca]n depends on the cell type. However, the cytosolic ET-1-induced increase of [Ca]n does not depend on cell type. In conclusion, nuclear membranes' ET-1 receptors may play an important role in overall ET-1 action. These nuclear membrane ET-1 receptors could be targets for a new generation of antagonists. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Recent work from our group showed that the nuclear envelope membranes contain several G protein-coupled receptors, including prostaglandin E2 (EP3R) and endothelin-1 (ET-1) receptors. Activation of EP3R increased endothelial nitric oxide synthase (eNOS) RNA expression in nuclei. eNOS and inducible NOS (iNOS) are reported to also be present at the nuclear level. Furthermore, reactive oxygen species (ROS) were also localized at the nuclear level. In this review, we show that stimulation with NO donor sodium nitroprusside results in an increase of intranuclear calcium that was dependent on guanylate cyclase activation, but independent of MAPK. This increase in nuclear calcium correlated with an increase in nuclear transcription of iNOS. H2O2 and ET-1 increase both cytosolic and nuclear ROS in human endocardial endothelial cells and in human aortic vascular smooth muscle cells. This increase in ROS levels by H2O2 and ET-1 was reversed by the antioxidant glutathione. In addition, our results strongly suggest that cytosolic signalization is not only transmitted to the nucleus but is also generated by the nucleus. Furthermore, we demonstrate that oxidative stress can be sensed by the nucleus. These results highly suggest that ROS formation is also generated directly by the nucleus and that free radicals may contribute to ET-1 regulation of nuclear Ca2+ homeostasis. Notre groupe a montré récemment que les membranes de l’enveloppe nucléaire contiennent plusieurs récepteurs couplés aux protéines G, dont les récepteurs de la prostaglandine E2 (EP3R) et de l’endothéline-1 (ET-1). L’activation des EP3R a augmenté l’expression de l’ARN de la monoxyde d’azote synthase endothéliale (eNOS) dans les noyaux. On a de plus signalé la présence de eNOS et iNOS au niveau nucléaire, et localisé des espèces réactives de l’oxygène (ROS) au même endroit. Dans la présente synthèse, nous montrons qu’une stimulation avec le donneur de NO nitroprussiate de sodium provoque une augmentation du calcium intranucléaire, qui est dépendante de l’activation de la guanylate cyclase, mais indépendante de la MAPK. Cette augmentation de calcium nucléaire est corrélée avec l’augmentation de la transcription nucléaire de iNOS. H2O2 et ET-1 augmentent les ROS tant cytosoliques que nucléaires dans les cellules endothéliales endocardiques et dans les cellules musculaires lisses vasculaires aortiques humaines. Cette augmentation des taux de ROS par H2O2 et ET-1 est renversée par l’antioxydant glutathion. De plus, nos résultats conduisent à penser que la signalisation cytosolique n’est pas seulement transmise au noyau, mais qu’elle est aussi générée par le noyau. Nous démontrons aussi que le stress oxydatif peut être perçu par le noyau. Ces résultats permettent de présumer que la formation de ROS est directement générée par le noyau, et que les radicaux libres pourraient contribuer à la régulation, par l’ET-1, de l’homéostasie du Ca2+ nucléaire. [ABSTRACT FROM AUTHOR]

We sought to examine the role of genetics in the multifactorial disease, abdominal aortic aneurysm (AAA), by studying sequence variation in the BAK1 gene ( BAK1) that codes for an apoptotic-promoting protein, as chronic apoptosis activation has been linked to AAA development and progression. BAK1 abdominal aorta cDNA from AAA patients and nondiseased individuals were compared with each other, as well as to the BAK1 genomic sequence obtained from matching blood samples. We found specific BAK1 single nucleotide polymorphism (SNP) containing alleles in both aneurysmic (31 cases) and healthy aortic tissue (5 cases) without seeing them in the matching blood samples. These same BAK1 SNPs have been reported, although rarely (average frequency <0.06%), in reference BAK1 DNA sequences. Based on this and other similar observations, we propose a novel hypothesis postulating that multiple variants of genes may preexist in 'minority' forms within specific nondiseased tissues and be selected for, when intra- and/or extracellular conditions change. Therefore, the fact that different BAK1 variants can exist in both diseased and nondiseased AA tissues compared to matching blood samples, together with the rare occurrence of these same SNPs in reference sequences, suggests that selection may be a significant factor in AAA ontogeny. Hum Mutat 30:1-5, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The use of confocal microscopy has shown that the nucleus plays an important role in excitation-contraction and excitation-secretion coupling of several excitable and nonexcitable cardiovascular cells. It has shown that the nuclear membranes, like the sarcolemmal membrane, possess ionic transporters as well as G protein-coupled receptors (GPCRs), which play a major role in modulating both cytosolic and nuclear ionic homeostasis and nuclear signalling. During spontaneous contraction of heart cells, the increase in cytosolic Ca2+ was immediately followed by a transient increase in nuclear Ca2+. The nuclear Ca2+ rise during excitation-contraction and excitation-secretion coupling was both dependent and independent of changes in cytosolic Ca2+. Nuclear membrane GPCRs, such as those of angiotensin II, neuropeptide Y, and ET-1, were functional and contributed to modulation of nuclear ionic homeostasis via direct and (or) indirect modulation of nuclear membrane ionic transporters such as channels, pumps, and exchangers. The signalling of nuclear membrane GPCRs may also contribute to modulation of gene expression, which may regulate proliferation and remodelling of cells and, indeed, life and death. Direct or indirect targeting of nuclear membrane ionic transporters and GPCRs may constitute a new target for drug action. L’utilisation de la microscopie confocale a permis de révéler que le noyau joue un rôle important dans le couplage excitation-contraction et excitation-sécrétion de plusieurs cellules cardiovasculaires excitables et non excitables. On a montré que, comme la membrane sarcolemmique, les membranes nucléaires possèdent des transporteurs ioniques et des récepteurs couplés aux protéines G (RCPG), qui jouent un rôle majeur dans la modulation de l’homéostasie ionique cytosolique et nucléaire ainsi que dans la signalisation nucléaire. Durant la contraction spontanée des cellules cardiaques, l’augmentation de Ca2+ cytosolique a été immédiatement suivie d’une augmentation transitoire de Ca2+ nucléaire. L’élévation du Ca2+ nucléaire durant le couplage excitation-contraction/sécrétion a été à la fois dépendante et indépendante des modifications du Ca2+ cytosolique. Les RCPG des membranes nucléaires, comme ceux de l’Ang II, de NPY et de l’ET-1, ont été fonctionnels et participent à la modulation de l’homéostasie ionique nucléaire par une modulation directe et/ou indirecte des transporteurs ioniques des membranes nucléaires, tels que les canaux, les pompes et les échangeurs. La signalisation des RCPG des membranes nucléaires pourraient aussi participer à la modulation de l’expression génique, qui pourrait réguler la vie et la mort ainsi que la prolifération et le remodelage des cellules. Le ciblage direct ou indirect des transporteurs ioniques et des RCPG des membranes nucléaires pourrait constituer une nouvelle cible pour l’action médicamenteuse. [ABSTRACT FROM AUTHOR]

Our previous work showed that ET-1 induced a concentration-dependent increase of cytosolic Ca2+ ([Ca]c) and nuclear Ca2+ ([Ca]n) in human aortic vascular smooth muscle cells (hVSMCs). In the present study, using hVSMCs and 3-dimensional confocal microscopy coupled to the Ca2+ fluorescent probe Fluo-3, we showed that peptidic antagonists of ETA and ETB receptors (BQ-123 (10-6 mol/L) and BQ-788 (10-7 mol/L), respectively) prevented, but did not reverse, ET-1-induced sustained increase of [Ca]c and [Ca]n. In contrast, nonpeptidic antagonists of ETA and ETB (respectively, BMS-182874 (10-8-10-6 mol/L) and A-192621 (10-7 mol/L)) both prevented and reversed ET-1-induced sustained increase of [Ca]c and [Ca]n. Furthermore, activation of the ETB receptor alone using the specific agonist IRL-1620 (10-9 mol/L) induced sustained increases of [Ca]c and [Ca]n, and subsequent administration of ET-1 (10-7 mol/L) further increased nuclear Ca2+. ET-1-induced increase of [Ca]c and [Ca]n was completely blocked by extracellular application of the Ca2+ chelator EGTA. Pretreatment with the G protein inhibitors pertussis toxin (PTX) and cholera toxin (CTX) also prevented the ET-1 response; however, strong membrane depolarization with KCl (30 mmol/L) subsequently induced sustained increase of [Ca]c and [Ca]n. Pretreatment of hVSMCs with either the PKC activator phorbol-12,13-dibutyrate or the PKC inhibitor bisindolylmaleimide did not affect ET-1-induced sustained increase of intracellular Ca2+. These results suggest that both ETA- and ETB-receptor activation contribute to ET-1-induced sustained increase of [Ca]c and [Ca]n in hVSMCs. Moreover, in contrast to the peptidic antagonists of ET-1 receptors, the nonpeptidic ETA-receptor antagonist BMS-182874 and the nonpeptidic ETB-receptor antagonist A-192621 were able to reverse the effect of ET-1. Nonpeptidic ETA- and ETB-receptor antagonists may therefore be better pharmacological tools for blocking ET-1-induced sustained increase of intracellular Ca2+ in hVSMCs. Our results also suggest that the ET-1-induced sustained increase of [Ca]c and [Ca]n is not mediated via activation of PKC, but via a PTX- and CTX-sensitive G protein calcium influx through the R-type Ca2+ channel. Nous avons démontré dans notre précédent travail que l’ET-1 induit une augmentation concentration dépendante du Ca2+ cytosolique ([Ca]c) et nucléaire ([Ca]n) dans les cellules musculaires lisses vasculaires aortiques humaines (CMLVh). Dans la présente étude, en utilisant des CMLVh et la microscopie confocale tridimensionnelle (3D) couplées à la sonde fluorescente au Ca2+, Fluo-3, nous montrons que les antagonistes peptidiques des récepteurs ETA et ETB (BQ-123 (10-6 mol/L) et BQ-788 (10-7 mol/L), respectivement) préviennent, mais ne renversent pas l’augmentation soutenue du [Ca]c et [Ca]n induite par l’ET-1. Toutefois, l’antagoniste non peptidique du récepteur ETA, BMS-182874 (10-8-10-6 mol/L), et l’antagoniste du récepteur ETB, A-192621 (10-7 mol/L), préviennent et renversent cette augmentation. De plus, l’activation du récepteur ETB au moyen de l’agoniste spécifique IRL-1620 (10-9 mol/L) induit des augmentations soutenues du [Ca]c et du [Ca]n, et l’ET-1 (10-7 mol/L) augmente davantage le Ca2+ nucléaire. L’augmentation du [Ca]c et du [Ca]n par l’ET-1 est totalement bloquée par l’application du chélateur du Ca2+, EGTA. En outre, un prétraitement avec les inhibiteurs des protéines G, PTX et CTX, prévient la réponse à l’ET-1; toutefois, une forte dépolarisation membranaire au moyen de 30 mmol/L de KCl induit une augmentation soutenue du [Ca]c et du [Ca]n. Un prétraitement avec l’activateur phorbol-12,13-dibutyrate ou l’inhibiteur de PKC bisindolylmaléimide n’affecte pas l’augmentation soutenue du Ca2+ intracellulaire induite par l’ET-1 dans les CMLVh. Ces résultats semblent indiquer que dans les CMLVh, l’activation des récepteur ETA et ETB contribue à l’augmentation soute [ABSTRACT FROM AUTHOR]

Bradykinin (BK) represents a pro-inflammatory mediator that partakes in many inflammatory diseases. The mechanism of action of BK is thought to be primarily mediated by specific cell surface membrane B2 receptors (B2Rs). Some evidence has suggested, however, the existence of an intracellular/nuclear B2R population. Whether these receptors are functional and contribute to BK signaling remains to be determined. In this study, by mean of Western blotting, 3D-confocal microscopy, receptor autoradiography and radioligand binding analysis, we showed that plasma membrane and highly purified nuclei from isolated rat hepatocytes contain specific B2R that bind BK. The results depicting B2R nuclear expression in isolated nuclear organelles were reproduced in situ on hepatic sections by immunogold labeling and transmission electron microscopy. Functional tests on single nuclei, by means of confocal microscopy and the calcium-sensitive probe fluo-4AM, showed that BK induces concentration-dependent transitory mobilization of nucleoplasmic calcium; these responses were blocked by B2R antagonist HOE 140, not by the B1R antagonist R954 and, were also found in wild-type C57/Bl6 mice, but not in B2R-KO mice. In isolated nuclei, BK elicited activation/phosphorylation of Akt, acetylation of histone H3 and ensuing pro-inflammatory iNOS gene induction as determined by Western blot and RT-PCR. ChIP assay confirmed binding of acetylated-histone H3 complexes, but not B2R, to promoter region of iNOS gene suggesting that B2R-mediated gene expression is bridged with accessory downstream effectors. This study discloses a previously undescribed mechanism in BK-induced transcriptional events, via intracrine B2R-mediated signaling, occurring in rat autologous hepatic cells. J. Cell. Physiol. 216: 234–244, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

To examine the role of endothelin ETA and ETB receptors in congestive heart failure due to cardiomyopathy, the effect of chronic treatment with selective ETA- and ETB-receptor antagonists (atrasentan and A-192621, respectively), alone and in combination, was assessed on functional and biochemical parameters of 52-week-old Bio 14.6 cardiomyopathic hamsters. Compared with control animals, cardiomyopathic hamsters treated for 9 weeks with atrasentan showed no variation in MAP; however, selective ETB- and combined nonselective ETA- and ETB-receptor antagonists increased systemic blood pressure. After selective ETB-receptor blockade, plasma endothelin levels were augmented. Importantly, this increase was highly enhanced (more than 8-fold) by concomitant ETA-receptor antagonism. Furthermore, the left ventricle : body weight ratio of cardiomyopathic hamsters treated with A-192621, alone or in combination with atrasentan, was significantly increased. On the other hand, decreased left ventricular end-diastolic pressure was observed in cardiomyopathic hamsters after selective ETA- or combined nonselective ETA/ETB-receptor antagonism, while only selective ETA-receptor blockade reduced left ventricular endothelin levels. Our results suggest that, in congestive heart failure, ETB receptors are essential to limit circulating endothelin levels, which may argue for improved cardiac benefits after long-term treatment with highly selective ETA-receptor antagonists. Pour examiner le rôle des récepteurs ETA et ETB de l’endothéline dans l’insuffisance cardiaque aiguë liée à une cardiomyopathie, on a évalué l’impact de traitements chroniques, d’une durée de 9 semaines, au moyen d’antagonistes sélectifs des récepteurs ETA (atrasentan) et ETB (A-192621), seuls ou combinés, sur les paramètres fonctionnels et biochimiques de hamsters cardiomyopathiques Bio 14,6 âgés de 52 semaines. Les hamsters cardiomyopathiques traités par atrasentan n’ont pas présenté de variation de la PAM comparativement aux animaux traités témoins. Toutefois, l’antagoniste sélectif des récepteurs ETB et les antagonistes sélectifs combinés des récepteurs ETA et ETB ont augmenté la pression artérielle systémique. Après le blocage sélectif des récepteurs ETB, les taux d’endothéline plasmatique ont augmenté. Point important, cette augmentation a été fortement accrue (de plus d’un facteur 8) par l’antagonisme concomitant des récepteurs ETA. De plus, le rapport poids ventriculaire gauche/poids corporel des hamsters cardiomyopathiques traités par A-192621, seul ou combiné avec l’atrasentan, a augmenté de manière significative. Par ailleurs, une diminution de la pression télédiastolique ventriculaire gauche a été observée chez les hamsters cardiomyopathiques après l’antagonisme sélectif des récepteurs ETA ou sélectif combiné des récepteurs ETA/ETB, alors qu’un blocage sélectif des récepteurs ETA seulement a réduit les taux d’endothéline ventriculaire gauche. Nos résultats donnent à penser que, dans l’insuffisance cardiaque congestive, les récepteurs ETB sont essentiels pour limiter les taux d’endothéline circulante, ce qui pourrait militer en faveur des effets bénéfiques d’un traitement à long terme par des d’antagonistes hautement sélectifs des récepteurs ETA. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In the vascular system, endothelin (ET) type B (ETB) receptors for ET-1 are located on endothelial and on venous and arterial smooth muscle cells. In the present study, we investigated the hemodynamic effects of chronic ETa receptor blockade at low and high doses in the Syrian Golden hamster. After 16 days of gavage with A-192621 (0.5 or 30 mg·kg-1·day-1 a selective ETB receptor antagonist, hamsters were anesthetized with a mixture of ketamine and xylazine (87 and 13 mg/kg im, respectively), and basal mean arterial blood pressure (MAP) and pressor responses to exogenous ET-1 were evaluated. The lower dose of A-192621 (0.5 mg·kg-1·day-1) did not modify basal MAP, whereas the higher dose (30 mg·kg-1·day-1) increased MAP and plasma ET levels. Radio-telemetry recordings confirmed the increase in MAP induced by the higher dose of A-192621 in conscious hamsters. On the other hand, although the lower dose of A-192621 was devoid of intrinsic pressor effects, it markedly reduced the transient hypotensive phase induced by intravenously injected IRL-1620, a selective ETB receptor agonist. Finally, A-192621 (0.5 mg·kg-1·day-1) alone or A-192621 (30 mg·kg-1·day-1) + atrasentan (6 mg·kg-1·day-1), a selective ETA receptor antagonist, potentiated the pressor response to exogenous ET-1. Our results suggest that, in the hamster, ETB receptors on vascular smooth muscle cells are importantly involved in the clearance of endogenous ET-1, whereas the same receptor type on the endothelium is solely involved in the vasodilatory responses to the pressor peptide. Blockade of endothelial and vascular smooth muscle cell ETB receptors triggers a marked potentiation of ETA-dependent increases in systemic resistance. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The use of an ET-1 fluorescent probe in human heart and vascular smooth muscle cells showed that ET-1 receptors are present at both the sarcolemma and nuclear envelope membranes. The use of immunofluorescence studies showed that the ET[subA] receptor was mainly present at the sarcolemma and cytosolic levels. However, the ET[subB] receptor was present at the sarcolemma and the cytosol, as well as the nuclear envelope membranes and the nucleoplasm. In addition, ET-1 immunoreactivity was seen in the cytosol and the nucleus. Using Ca&sup2+;fluorescent probes such as Fluo-3, Indo 1, and yellow cameleon, as well as confocal microscopy three-dimensional image measurement technique, stimulation of ET-1 receptors at the sarcolemma membranes induced an increase of cytosolic and nuclear free Ca&sup2+; levels. This effect of extracellular ET-1 was blocked by removal of extracellular calcium. Direct stimulation of ET-1 receptors at the nuclear envelope membranes also induced an increase of intranuclear free Ca&sup2+; level. Our results suggest that the stimulation of sarcolemmal Ca&sup2+; influx by ET-1 seems to be due to the activation of ET[subA] and ET[subB] receptors. However, the increase of nucleoplasmic Ca&sup2+; levels by cytosolic ET-1 seems to be mediated via the activation of ET[subB] receptors. Activation of nuclear membranes ET[subB] receptors seems to prevent nuclear Ca&sup2+; overload and may protect the cell from apoptosis. [ABSTRACT FROM AUTHOR]

Focuses on a study which examined the chronotropic effect of bradykinin on cytosolic and nuclear free calcium ions. Materials and methods; Results; Discussion.

Deals with a study which examined the effects of the adrenergic receptor agonist called methoxamine and the autoantibody directed against the second extracellular loop of α[sub1]-adrenoceptros on intracellular free calcium ion levels. Materials and methods; Results; Discussion.

Provides information on a study that investigated the potential beneficial effect of chronic treatment with a dual L-type Ca²&sup+; and slow Na&sup+; channel blockers isradipine, on the development of necrosis in myopathic hamster hearts. Methodology of the study; Results and discussion on the study.

Introduces the discovery of functional G-protein-coupled receptors for prostanoids, namely EP receptors, at the nuclear membrane and describes their signaling pathways. Biogenesis of prostanoids; Discussion on prostaglandin signal transduction network at the nucleus; Conclusions.

1 Endothelin-l(1-31) (ET-I(1-31); 0.25 to 4 nmol kg[sup -1]; i.v.) induced, in the guinea-pig, graded increases in MAP and an indomethacin-sensitive enhancement of pulmonary insufflation pressure (PIP). At all doses, ET-1(1-31) induced a monophasic pressor response, except at 4 nmol kg[sup -1], which caused a rapid and transient response (first phase: over first 10 min after injection) followed by a more slowly-developing and sustained (second phase: between 10 and 45 min after injection) increase in MAP. ET-1(1-31) was 4 to 10 fold less potent than ET-1 on PIP responses. 2 Phosphoramidon (5 and 10mg kg[sup -]) reduced both pressor and PIP effects of ET-1(1-31). Thiorphan (0.25 and 2.5 mg kg[sup -1]) did not affect the pressor responses to ET-1(1-31) although its PIP effects were markedly reduced by the NEP inhibitor. A selective endothelin-converting enzyme (ECE) inhibitor, CGS 35066 (1 mg kg[sup -1]), significantly reduced the second phase pressor response and increase in PIP triggered by ET-1(1-31). 3 The second (but not the first) pressor phase of ET-1(1-31) (4 nmol kg[sup -1]) was markedly reduced by BQ-123 (selective ETA antagonist), whereas the increase of PIP was significantly reduced by BQ788 (selective ET[sub B] antagonist). Co-administration of BQ-123 plus BQ-788 abolished ET-1(1-31)induced increase in PIP, but blockade of the second pressor phase afforded by BQ-123 was now reversed. 4 In guinea-pig isolated perfused lungs, ET-1(1-31) (50 nM) induced the release of prostacyclin and thromboxane A[sub 2], which was inhibited by BQ-788 (5 nM) or thiorphan (25 µM), but not BQ-123 (1 µM). 5 These results suggest that ET-1(1-31) enhances MAP. Its sustained, but not transient, pressor effects are mediated via ETA receptor activation. Furthermore, ET-1(1-31) increases airway resistance in vivo and triggers prostacyclin and thromboxane A[sub 2] release from perfused lungs predominantly via ET[sub B] receptor activation. ET-1(1-31) failed to... [ABSTRACT FROM AUTHOR]

The relationships between changes in intracellular Ca&sup2+; and smooth muscle tension triggered by endothelin-1 and the selective endothelin ET[subB] receptor agonist sarafotoxin S6c, as well as their susceptibility to modification by the nonselective cyclooxygenase blocker indomethacin, were assessed in guinea pig isolated gallbladder strips. Cumulative additions of either agonist (1, 10, and 100 nM) induced simultaneous graded, strongly correlated, slowly developing, and sustained changes in tension and intracellular Ca&sup+2; (Fura-2 technique). Sarafotoxin S6c was more effective than endothelin-1 in raising intracellular Ca&sup2+; at 1 or 10 nM, but their abilities to cause contractions were similar at all concentrations. Indomethacin (5.6 μM) markedly inhibited the changes in both intracellular Ca&sup2+; and tension caused by all concentrations of sarafotoxin S6c (in response to 100 nM, increases in Ca[sub+2] fluorescence intensity and tension were inhibited from 7.7 ± 0.7 to 4.0 ± 0.4% and from 460 ± 100 to 160 ± 40 mg, respectively) but only reduced the contraction triggered by 100 nM endothelin-1 (from 560 ± 100 to 230 ± 70 mg). Endothelin-1 caused greater prostacyclin release from gallbladder than sarafotoxin S6c (at 100 nM, 6-keto-PGF[sub1α] levels in the medium rose 4.8- and 2.8-fold, respectively; P < 0.05) and slightly increased thromboxane A[sub2] release (1.6-fold; P < 0.05). Thus, gallbladder contractions triggered by combined ET[subA] /ET[subB] or selective ET[subB] receptor stimulation (with endothelin-1 or sarafotoxin S6c, respectively) are strongly correlated with increases in intracellular Ca[sub2+] but differentially affected by indomethacin. It remains... [ABSTRACT FROM AUTHOR]

1 In the present study, the properties of endothelin-1 (ET-1) and platelet-activating factor (PAF) in inducing contraction and increased intracellular-free calcium level in rat mesenteric arteries and veins were studied. Furthermore, measurements of cytosolic ([Ca][sub c]) and nuclear ([Ca][sub n]) Ca[sup 2+] were performed by confocal microscopy. 2 PAF, at a concentration of 1 µM, and the selective ET[sub B] agonists, IRL-1620 and sarafotoxin S6C (100 nM), induced a marked constriction and increase in [Ca][sub i] in the mesenteric vein but not in the artery. On the other hand, endothelin-1 (1-100 nM) induced a significant concentration-dependent nifedipine-insensitive increase in tension and [Ca][sub i] in both arteries and veins. 3 Those responses to endothelin-1 were significantly reduced by the ETA receptor antagonist, BQ123 (10[sup -6] M), on both types of vessels, whereas the selective ET[sub B] receptor antagonist, BQ-788, inhibited only the venous responses. The mixed ET[sub A]/ET[sub B] receptor antagonist, SB 209670, reduced the ET-1-induced venous responses to the same level of that found in presence of BQ-123 or BQ788. However, concomitant applications of BQ-123 and BQ-788 reduced the vasoconstriction below to that induced by ET[sub A] or ET[sub B] blockade without further affecting [Ca][sub i]. 4 PAF and the selective ET[sub B] agonists IRL-1620, induced a sustained increase of [Ca][sub c] and [Ca][sub n] solely in venous cells and ET-1 in both arterial and venous smooth muscle cells. 5 Thus, PAF increases total intracellular calcium concentration and tension on the smooth muscle cells from venous origin only. Furthermore, ET-1-induced vasoactive as well as [Ca][sub i] and [Ca][sub n] increasing effects are mediated by distinct receptors on venous and arterial smooth muscles. [ABSTRACT FROM AUTHOR]